JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
VOL. 64, NO. 12, 2014
ª 2014 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 0735-1097/$36.00
PUBLISHED BY ELSEVIER INC.
http://dx.doi.org/10.1016/j.jacc.2014.06.1193
THE PRESENT AND FUTURE
STATE-OF-THE-ART REVIEW
Triple Therapy for Atrial Fibrillation and
Percutaneous Coronary Intervention
A Contemporary Review
Willem J.M. Dewilde, MD,* Paul W.A. Janssen, MD,y Freek W.A. Verheugt, MD, PHD,z
Robert F. Storey, MD, PHD,x Tom Adriaenssens, MD, PHD,k Morten L. Hansen, MD, PHD,{
Morten Lamberts, MD, PHD,{ Jurriën M. ten Berg, MD, PHDy
ABSTRACT
Chronic oral anticoagulant therapy is recommended (class I) in patients with mechanical heart valves and in patients with
atrial fibrillation with a CHA2DS2-VASc (Congestive heart failure, Hypertension, Age $75 years, Diabetes mellitus, prior
Stroke or transient ischemic attack or thromboembolism, Vascular disease, Age 65 to 74 years, Sex category) score $1.
When these patients undergo percutaneous coronary intervention with stenting, treatment with aspirin and a P2Y12
receptor inhibitor also becomes indicated. Before 2014, guidelines recommended the use of triple therapy (vitamin K
antagonists, aspirin, and clopidogrel) for these patients. However, major bleeding is increasingly recognized as the
Achilles’ heel of the triple therapy regimen. Lately, various studies have investigated this topic, including a prospective
randomized trial, and the evidence for adding aspirin to the regimen of vitamin K antagonists and clopidogrel seems to be
weakened. In this group of patients, the challenge is finding the optimal equilibrium to prevent thromboembolic
events, such as stent thrombosis and thromboembolic stroke, without increasing bleeding risk. (J Am Coll Cardiol
2014;64:1270–80) © 2014 by the American College of Cardiology Foundation.
C
hronic oral anticoagulation (OAC) is neces-
antiplatelet therapy (DAPT) with aspirin and clopi-
sary in patients with mechanical heart
dogrel becomes indicated to prevent stent thrombosis
valves and in patients with atrial fibrillation
(3–5).
(AF) and a CHA 2DS2VASc (Congestive heart failure,
In a rapidly aging population, the number of pa-
Hypertension, Age $75 years, Diabetes mellitus, prior
tients experiencing both AF and CAD is steadily
Stroke or transient ischemic attack or thromboembo-
increasing. However, triple therapy produces a high
lism, Vascular disease, Age 65 to 74 years, Sex cate-
annual bleeding risk of up to 45%, and an association
gory) score $1 (1,2). About 30% of these patients
has been seen among major bleeding events, blood
have concomitant coronary artery disease (CAD).
transfusion, and increased mortality risk (6–11). Triple
When these patients have to undergo percutane-
therapy, including vitamin K antagonists (VKAs),
ous coronary intervention (PCI), additional dual
aspirin, and clopidogrel (for as short a time as
From the *Department of Cardiology, Amphia Hospital, Breda, the Netherlands; yDepartment of Cardiology, St Antonius Hospital,
Nieuwegein, the Netherlands; zDepartment of Cardiology, Onze Lieve Vrouwe Hospital (OLVG), Amsterdam, the Netherlands;
xDepartment of Cardiovascular Science, University of Sheffield, Sheffield, United Kingdom; kDepartment of Cardiology, Gasthuisberg University Hospital Leuven, Leuven, Belgium; and the {Department of Cardiology, Copenhagen University Hospital
Gentofte, Copenhagen, Denmark. Dr. Dewilde has received speakers fees from AstraZeneca and Sanofi. Dr. Verheugt has received
consultant fees/honoraria from Bayer Healthcare, AstraZeneca, and Boehringer Ingelheim. Dr. Storey has received consultancy
fees, honoraria, and/or institutional research grants from Accumetrics, AstraZeneca, Correvio, Daiichi Sankyo, Merck, PlaqueTec,
Regeneron, Roche, and Sanofi-Aventis. Dr. ten Berg has received speakers’ fees from AstraZeneca, Merck, and Lilly; and has
received a research grant from AstraZeneca. All other authors have reported that they have no relationships relevant to the
contents of this paper to disclose.
Manuscript received March 29, 2014; revised manuscript received June 18, 2014, accepted June 30, 2014.
Dewilde et al.
JACC VOL. 64, NO. 12, 2014
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Triple Therapy for AF and PCI
possible), was recommend by the 2010 European
event. At 1 year, the cumulative incidence of
ABBREVIATIONS
guidelines, whereas the recent 2014 North American
all Thrombolysis In Myocardial Infarction
AND ACRONYMS
Guidelines recommend the combination of VKA and
(TIMI) bleeding events was 19.4% in the dual-
clopidogrel with a Class IIb, Level of Evidence: B
therapy group compared with 44.4% in pa-
recommendation (4,12). The 2010 European guidelines
tients treated with triple therapy (hazard
were based on expert opinion and not on randomized
ratio [HR]: 0.36; 95% confidence interval [CI]:
trials (4). Recently, new evidence has emerged sug-
0.26 to 0.50; p < 0.0001) (6,21). The 1-year
gesting that the increased bleeding risk outweighs the
incidence of serious bleeding according to
efficacy (preventing stent thrombosis, myocardial
Bleeding
Academic
Research
Consortium
ACS = acute coronary
syndrome(s)
AF = atrial fibrillation
BARC = Bleeding Academic
Research Consortium
DAPT = dual antiplatelet
therapy
infarction [MI], stroke, and thromboembolism) benefit
(BARC) criteria 3 also was significantly lower
of triple therapy in these patients, and possibly, a new
in the dual therapy arm (6.5% vs. 12.7%;
heparin
strategy of VKA and a P2Y 12 inhibitor alone could be
HR: 0.49; 95% CI: 0.28 to 0.86; p ¼ 0.011)
OAC = oral anticoagulation
preferred (6,12–15). This review will summarize
(6,22). Furthermore, dual therapy produced a
PCI = percutaneous coronary
guidelines, focus on some key evidence from the last
significantly lower rate of blood transfusions
intervention
several years, and address unanswered questions.
than did triple therapy (3.9% vs. 9.5%; odds
PPI = proton pump inhibitor
GUIDELINES
European guidelines recommend triple antithrombotic therapy in a patient with AF undergoing PCI
(4). This triple therapy consists of VKA with a
revised target for international normalized ratio (INR)
2.0 to 2.5, aspirin, and clopidogrel. Aspirin has always
been the cornerstone in treating patients with acute
coronary syndrome (ACS) and/or PCI, VKAs are
needed for stroke prevention, and a P2Y12 inhibitor is
essential for the prevention of stent thrombosis
(16–19). However, this triple therapy strategy has
never been studied prospectively until the recent
WOEST (What is the Optimal antiplatElet and anticoagulant
therapy
in
patients
with
oral
anti-
coagulation and coronary StenTing) trial (6).
European guidelines recommend continuing VKAs
and giving triple therapy for as short a period as
possible after PCI, in general until stent strut endothelialization is expected to be complete. The duration of prescribed triple therapy mostly depends on
bleeding risk and stent type, and various recommendations are made to limit bleeding risk, as
mentioned below.
Recently, following the results of the WOEST trial,
the American Heart Association/American College of
Cardiology/Heart Rhythm Society issued a Class IIb
(Level of Evidence: B) recommendation for the
combination of VKA and clopidogrel after PCI in
patients with AF (12).
NEW EVIDENCE
LMWH = low molecular weight
ratio [OR]: 0.39; 95% CI: 0.17 to 0.84;
TIMI = Thrombolysis In
p ¼ 0.011). Secondary endpoints included
Myocardial Infarction
major adverse cardiac and cerebrovascular
events (MACCE) defined as the composite of
death, MI, stroke, systemic embolism, target
TVR = target vessel
revascularization
UFH = unfractionated heparin
vessel revascularization (TVR), and stent thrombosis,
which occurred in 11.1% of patients receiving dual
therapy compared with 17.6% of patients receiving
triple therapy (HR: 0.60; 95% CI: 0.38 to 0.94;
p ¼ 0.025). The WOEST trial indicates that double
therapy (VKA and clopidogrel without aspirin) significantly reduces bleeding complications as compared with triple therapy after PCI in patients with
an indication for OAC. Dropping aspirin in this highrisk group led to a more than 50% reduction in the
occurrence of bleeding complications.
After the WOEST trial results were published,
expert opinion was that it was too early to change the
guidelines, even though current recommendations
are not based on randomized trials (23). The reasons
given for the reluctance to change guidelines were
based on the limitations of the WOEST trial. First, the
number of patients randomized was relatively low
(n ¼ 573) and not every patient had AF (approximately 70%). Second, there was no significant difference in TIMI major bleeding, and the absolute
number of major bleeds was rather low (16 vs. 9). The
difference in bleeding was mainly driven by TIMI
minor bleeding. However, when bleeding events
were classified according to the new standardized
BARC bleeding criteria, there was a significant difference in BARC 3 bleeding, which corresponds with
major bleeding, in favor of the combination of clo-
In the randomized, controlled WOEST trial, 573 pa-
pidogrel and VKA (6,22). Additionally, the authors
tients using VKA undergoing PCI in an open-label,
emphasized the importance of minor bleeding,
intention-to-treat design were randomized to either
because these events can lead to cessation of medi-
double therapy (VKA and clopidogrel) or triple ther-
cation (e.g., clopidogrel) and major adverse events
apy (VKA, clopidogrel, and aspirin) (6,20). The pri-
such as stent thrombosis (6). Third, compared with
mary endpoint was the occurrence of any bleeding
current recommendations, the rate of proton pump
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Triple Therapy for AF and PCI
inhibitor (PPI) use at baseline was low (37%), the
with a significant increase in all-cause mortality
radial approach was used infrequently (26%), bare-
compared with triple therapy (13).
metal stents (BMS) were used in a minority of pa-
The most important aspect of the Danish registry:
tients (31%), periprocedural target INR was 2.0, and
it suggests that the combination of OAC plus clopi-
the long-term target INR was not lowered post-
dogrel is sufficient to reduce the risk of thrombotic
procedurally (target INR 2 to 3 for AF). These results
events. This was the missing part of the puzzle, since
are compared with current guidelines, which recom-
the WOEST trial was not powered to show non-
mend standard PPI use, radial approach, BMS use, and
inferiority on the secondary composite MACCE end-
a lower long-term target INR of 2 to 2.5 in this patient
point. Also, the Danish registry is now the second
population. The conflict with the guidelines is easily
study in which no beneficial effect of adding aspirin
explained: in 2008, when the WOEST study was
to VKA and clopidogrel was found in this high-risk
designed, these recommendations were not available
patient group. The authors explain that the bleeding
yet (4,12). Fourth, the number of deaths was signifi-
rate was lower in the VKA plus clopidogrel patient
cantly higher with triple therapy, but this was driven
group, but this difference did not reach statistical
by a higher number of noncardiac deaths, which might
significance, likely because this registry only in-
be due to a play of chance. Fifth, there was no infor-
cluded bleeding events serious enough to warrant
mation on the time of INR in the therapeutic range.
hospitalization, whereas all bleeding events were
However, we know from the RE-LY (Randomized
collected in the WOEST trial.
Evaluation of Long-Term Anticoagulation Therapy)
Two other registries that confirmed the efficacy
trial that the quality of oral anticoagulation is good in
and safety of VKA plus clopidogrel in patients with AF
the Netherlands and Belgium, with a therapeutic
who underwent PCI were recently published. In the
range of 65% for patients treated in Belgium and up to
AFCAS
70% in the Netherlands (24). Finally, the study was
Stenting) trial, a prospective nonrandomized study
not powered to show noninferiority of the secondary
including 975 patients, the 1-year efficacy and safety
outcomes and the number of patients at high risk of
of triple therapy, DAPT, and VKA plus clopidogrel was
stent thrombosis, such as those with recent ACS, was
comparable (15). A total of 221 patients who received
limited to a quarter of the WOEST trial participants.
drug-eluting stenting (DES) were included in another
The study population was heterogeneous, because
German registry with a mean follow-up of 19 months.
the goal was to conduct a trial with a real-life popu-
Despite a shorter period of clopidogrel therapy (6 to
lation representing daily practice (6). Moreover, the
12 months) followed by VKA monotherapy, the com-
WOEST trial was the first to break the taboo of omit-
bination of OAC plus clopidogrel again appeared both
ting treatment with aspirin after PCI, hypothesizing
safe and effective at long-term follow-up (14).
(Atrial
Fibrillation
Undergoing
Coronary
that inhibition of thrombin (a strong platelet activator) with VKA and inhibition of the P2Y 12 receptor
CLINICAL IMPORTANCE AND PREVENTION
with clopidogrel would make inhibition of cyclo-
OF BLEEDING AFTER PCI
oxygenase-1 less important in the protection against
thrombotic and thromboembolic events, particularly
Major bleeding events and blood transfusions have
since the P2Y12 receptor plays a major role in ampli-
been associated with increased risk of death in
fying the effects of thromboxane A2.
several studies (7,8,25–28). This has led to an in-
Recently, a Danish group published results of a real-
creased awareness of this problem, and predictors
life nationwide retrospective registry of 12,165 pa-
of bleeding events in PCI patients have been identi-
tients that supported the findings in the WOEST trial
fied. Strong predictors we can influence are the
(13). The authors investigated the risk for thrombosis
choice of vascular access (radial vs. femoral) and the
and bleeding according to multiple antithrombotic
choice of antithrombotic regimen (28–31).
regimens after MI or PCI in AF patients. After 1 year,
The importance of bleeding as an adverse event
there was no increased risk of recurrent coronary
is underscored by the fact that bleeding has now
events for dual therapy (HR: 0.69; 95% CI: 0.48 to 1.00)
become a primary endpoint in many PCI trials
relative to triple therapy, and bleeding risk was also
(7,17,28,32,33). In an effort to standardize the defini-
nonsignificantly lower for VKA plus clopidogrel (HR:
tion and detection of bleeding events in different
0.78, 95% CI: 0.55 to 1.12). Moreover, there was a
studies, the Academic Research Consortium pub-
similar risk for all-cause mortality in patients treated
lished and validated new bleeding criteria (BARC)
with VKA plus clopidogrel as well as those receiving
(22,34). Before the BARC criteria were established,
triple therapy, but the combinations of VKA plus
different trials used different bleeding definitions,
aspirin and aspirin plus clopidogrel were associated
which was an important hindrance when trying to
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Triple Therapy for AF and PCI
compare bleeding rates across trials (21,35). A second
to avoid and prevent bleeding, such as the standard-
obstacle when assessing bleeding rates is the possible
ized use of a risk score assessment tool, a radial
under-reporting of bleeding events in studies (36).
approach, smaller sheath size and early removal, BMS
Therefore, the impact of bleeding could be even
use, routine use of PPI, utilization of a target INR
larger in real life than reported in these studies. This
range of 2.0 to 2.5, the choice and dose of antith-
could also explain why the bleeding rate reported in
rombotics and P2Y12 inhibitors, and avoidance of all of
the WOEST trial stood very high compared to other
the following: crossing over from 1 antithrombotic to
trials, as this study was specifically designed to
another, an intra-aortic balloon pump, use of glyco-
detect bleeding events and data were collected for all
protein
types of bleeding rather than solely focusing on ma-
bridging with LMWH if not strictly indicated (4,12,28).
IIb/IIIa
inhibitors,
and
periprocedural
jor bleeding events (6).
Another issue that needs to be addressed: patients
PERIPROCEDURAL MANAGEMENT
with AF in need of PCI represent a population that
mainly consists of older patients with high rates
Besides the choice between dual or triple therapy,
of comorbidity. Many are octogenarians, a group
another decision looms for patients on OAC who have a
frequently excluded from or under-represented in
planned PCI: what to do with the VKA in the peri-
randomized clinical trials. It is questionable whether
procedural period? In patients on a VKA scheduled for
our current guidelines can be applied to this group.
PCI, the VKA is often discontinued several days prior
Additionally, we know that older patients with AF
to intervention, exposing the patient to a higher risk of
have a higher CHA 2DS2 -VASc score as well as a higher
thromboembolic complications. Occasionally, the pe-
bleeding risk when treated with VKAs (37). In this
riods before and after the intervention are bridged
population, the role of nonmajor bleeding should not
(until a therapeutic INR is reached) with additional
be underestimated. Even superficial or “nuisance”
unfractionated heparin or LMWH, exposing the pa-
bleeding can lead to discontinuation of antiplatelet
tient to excess bleeding risk. When patients are treated
therapy, which can lead to subsequent thrombotic
with 4 blood thinners (OAC, clopidogrel, aspirin, and
complications, such as stent thrombosis. Clearly, this
heparin) for a short period after the intervention until
high-risk population, often with multiple comorbid-
a therapeutic INR is reached, the bleeding risk is
ities, is more prone to experience treatment-related
particularly high (43). Additionally, reinitiation of VKA
adverse events (4,38).
may cause a transient prothrombotic state due to
Over the last years, numerous risk factors have
protein C and S suppression (4). Bridging also prolongs
been associated with higher bleeding risk: age
hospitalization, which is unnecessary and wasteful
>55 years, female sex, glomerular filtration rate <60
from an economic point of view.
ml/min, pre-existing anemia, use of low-molecular-
Recent European guidelines recommended unin-
weight heparin (LMWH) <48 h before PCI, use of
terrupted VKA as the preferred strategy in patients
glycoprotein IIb/IIIa inhibitors, and the use of an
with AF undergoing PCI (4). In the AFCAS trial and in
intra-aortic balloon pump (27,39,40).
a recent subanalysis of the WOEST trial, uninter-
To estimate bleeding risk, many bleeding risk–
rupted OAC was not associated with an increased risk
prediction scores have been proposed, and the best
of bleeding or thromboembolic events compared
known is the HAS-BLED score (41). The HAS BLED
with bridging therapy (43,44). Furthermore, bleeding
score estimates the risk for major bleeding for patients
and other adverse events were not associated with
on anticoagulation and is based on the presence of
INR levels in these studies (43,44). Additional sup-
some high-risk features as hypertension, stroke, renal
port comes from the BAAS (Prospective Balloon
disease, liver disease, prior major bleeding, age older
Angioplasty and Anticoagulation) study, where the
than 65 years, labile INR, the use of medication pre-
combination of aspirin plus VKA compared with
disposing to bleeding and weekly alcohol usage.
aspirin alone was safe and effective during PCI per-
Shown to be useful in the assessment of bleeding risk,
formed with a target INR of 2.1 to 4.8 (45). So, the
the HAS-BLED score also demonstrates some predic-
strategy of uninterrupted VKA not only leads to cost
tive value for cardiovascular events and mortality in
savings, but it is also as safe as bridging and, there-
anticoagulated patients with AF. The data are
fore, may be the preferred strategy.
consistent with the relationship between thrombosis
Similarly, the radial approach offers the better
and bleeding and confirm that the number of bleeding
strategy in these patients based on proven lower
and thrombotic events is higher in patients with high
rates of bleeding and a possible reduction in mortal-
comorbidity at baseline (42). The higher the patient’s
ity, especially in ST-segment elevation myocardial
bleeding risk, the more measures should be taken
infarction patients (30). One question regarding the
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Triple Therapy for AF and PCI
periprocedural strategy remains unanswered. Like
15% of the variability accounted for by polymorphic
coronary angiography, it might be an option to per-
variations in the gene for cytochrome P450 2C19
form
additional
(52–54). Patients who have a poor inhibitory effect of
heparin in patients on therapeutic anticoagulation
clopidogrel and/or carry 1 or more loss-of-function
with a VKA (46). However, physicians did not avoid
alleles for cytochrome P450 2C19 are at higher risk
an additional heparin bolus during PCI in most
of stent thrombosis, whereas those with a large
patients included in the WOEST trial. This strategy
inhibitory effect of clopidogrel appear to hold a
was probably chosen due to fear of periprocedural
higher risk of bleeding. This potentially complicates
thromboembolic complications such as stent throm-
the interpretation of data related to dual antiplatelet
bosis (43). On the one hand, this additional heparin
therapy with clopidogrel and VKA, because levels of
bolus
higher-than-expected
platelet reactivity may vary widely between patients.
bleeding rates in the original WOEST trial (6). In the
For example, patients with a poor response to clo-
AFCAS study, 48% of patients also received a pre-
pidogrel who develop a low INR may be at higher risk
procedural bolus of heparin or LMWH in addition
of stent thrombosis and other thrombotic events,
to therapeutic anticoagulation in the uninterrupted
whereas patients with a large inhibitory effect of
VKA group (44). On the other hand, a recently pub-
clopidogrel who develop a high INR may be at higher
lished study showed that the incidence of radial
risk of bleeding (52–54).
PCI
without
could
administration
explain
the
of
artery occlusion in patients receiving VKA who un-
A third conceivable pitfall is the possibility that
dergo transradial coronary angiography is higher in
VKA itself might modify clopidogrel drug respon-
patients who do not receive an additional standard
siveness and efficacy. Both clopidogrel and VKA are
intravenous unfractionated heparin bolus (47). As of
metabolized by the hepatic cytochrome P450 system.
yet, there is insufficient evidence to determine if
Concomitant phenprocoumon use has been shown to
a heparin bolus is necessary in patients with thera-
significantly attenuate the antiplatelet effects of
peutic INR requiring PCI. Furthermore, it is unclear
clopidogrel and has been associated with a signifi-
what the optimal dosage would be if a heparin bolus
cantly higher level of high on-platelet reactivity
is indeed necessary.
(HPR) (55). While HPR has been linked with a poor
outcome, it is still unknown if the association be-
POSSIBLE PITFALLS AND OTHER
tween HPR and thrombotic events is as strong in
UNANSWERED QUESTIONS
patients concomitantly treated with coumarin derivates as in patients who do not receive these
In patients treated with triple therapy, bleeding oc-
drugs. Furthermore, there currently is no evidence
curs frequently in the gastrointestinal tract, making
for tailoring antiplatelet therapy based on the pres-
protection of the gastric mucosa reasonable. Yet,
ence of HPR (53). Although switching from clopi-
some papers have suggested that there is a potential
dogrel to the stronger antiplatelet agents prasugrel or
danger in combining omeprazole and clopidogrel
ticagrelor might be an option in HPR patients without
due to impairment in the formation of the active
VKA, it is even more unclear what the optimal
metabolite of clopidogrel by omeprazole, leading
treatment strategy could be for HPR patients with
to diminished antiplatelet effect (48,49). However,
VKA (53). Theoretically, ticagrelor and prasugrel
no clinical consequences of this interaction have
could be good alternatives for clopidogrel as they
been demonstrated so far. The single randomized
provide more potent platelet inhibition with less
controlled trial on this topic, COGENT (Clopidogrel
interindividual variability (56,57). However, bleeding
and the Optimization of Gastrointestinal Events
risk also increases with treatment with ticagrelor
Trial), showed that in patients post-ACS, the combi-
and prasugrel as compared with clopidogrel (56,57).
nation of omeprazole 20 mg and clopidogrel 75 mg
The fourth and very important question to tackle:
was superior to the combination of clopidogrel and
why would we want to replace the combination of
placebo in reducing the rate of gastrointestinal
DAPT plus VKA with the combination of VKA plus
bleeding, with no significant difference in the rate of
clopidogrel? Since 2001, DAPT has been standard
adverse cardiovascular events (50). Subsequent re-
therapy after PCI. The CURE (Clopidogrel in Unstable
ports have suggested that PPI use should not be
Angina to Prevent Recurrent Events) study included
avoided but rather encouraged in patients on multi-
12,562 patients who had presented within 24 h after
ple antiplatelet medications (49,51).
ACS without ST-segment elevation and were ran-
A second possible pitfall for clopidogrel is the
domized to receive either clopidogrel or placebo in
wide interindividual variability to the drug, even in
addition to aspirin. Clopidogrel had beneficial effects
the absence of any drug interactions, with 12% to
because of a significant reduction in MACCE (9.3% vs.
Dewilde et al.
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Triple Therapy for AF and PCI
11.4%; p < 0.001) (58). So then, why would we try to
unopposed thromboxane-dependent platelet activa-
replace aspirin with VKA? In these patients who also
tion after stopping aspirin is clinically meaningful in
need VKA for stroke prevention, there are many
the present patient population. It is possible that the
possible therapeutic combinations, but it has already
negative
been shown that the combination of VKA plus aspirin
dependent platelet activation is overruled by the
(leaving out clopidogrel) led to an increased rate of MI
anticoagulant effect of VKA and the antiplatelet
and stent thrombosis (13,18). In the ACTIVE W (Atrial
effect of clopidogrel.
impact
of
unopposed
thromboxane-
Fibrillation Clopidogrel Trial With Irbesartan for Pre-
The sixth unanswered question in patients on
vention of Vascular Events) study, withholding VKA
long-term VKA who received a coronary stent is: how
(thus treating patients only with aspirin and clopi-
should we treat patients after clopidogrel is dis-
dogrel) in patients with AF led to an increased rate of
continued (after 3, 6, or 12 months of treatment)? Do
cardiovascular events and mortality (16). This leaves
you treat patients with a combination of VKA and
triple therapy and the combination of VKA and clo-
aspirin because of CAD, or is VKA monotherapy
pidogrel as the only alternatives.
enough
to
protect
patients
against
thrombotic
But then, why drop aspirin? The hypothesis of the
events? In the absence of randomized trials, we turn
WOEST trial was that thrombin inhibition with VKA
to 2 large registries: a recently published Danish
and inhibition of P2Y 12 with clopidogrel would lessen
registry containing 8,700 patients and ORBIT-AF
the importance of cyclo-oxygenase-1 inhibition by
(Outcomes Registry for Better Informed Treatment
aspirin for protection against thrombotic and throm-
of Atrial Fibrillation), in which 4,804 patients taking
boembolic events, whereas triple therapy has been
VKAs were compared with 2,543 patients taking OAC
associated with an increased risk of both fatal and
plus aspirin. In both registries, the combination of
nonfatal bleeding (6,7,59,60). This hypothesis was
based on the results of 2 large randomized trials that
compared VKA with aspirin in the prevention of
reinfarction and stroke in patients who had experienced an MI. Vitamin K antagonist treatment was
associated with lower recurrence rates but higher
risks of bleeding in these studies (61,62). Therefore,
VKA seems at least as good as aspirin in protecting
patients from thrombotic events. The hypothesis that
aspirin is not needed in VKA-treated patients who
undergo PCI with stent implantation is supported by
Clopidogrel
(Antiplatelet,
stent thrombosis
inhibitor,
P2Y12 inhibitor)
the results of the WOEST trial. Nevertheless, the
WOEST trial was not powered to detect differences in
the occurrence of thrombotic events, such as stent
thrombosis, when aspirin was omitted, and this
would need to be studied in a larger trial. Meanwhile,
these results were confirmed by a large Danish national registry, the AFCAS trial, and a smaller German
DUAL:
Increased
rates of
cardiovascular
events and
mortality
DOUBLE:
Sufficient to
prevent thrombosis,
reduced major
bleeding complications,
no increased risk of recurrent
coronary events after 1 year
TRIPLE:
High rates of
bleeding events,
bleeding complications,
blood transfusions,
major adverse cardiac
and cerebrovascular
events (MACCE),
and death
Vitamin K
antagonists (VKA)
(Anticoagulant,
stroke prevention)
DUAL:
Increased
rates of stent
thrombosis and
myocardial
infarction
trial all showing favorable results for the combination
of VKA and clopidogrel (6,13–15) (Central Illustration).
The fifth dilemma focuses on how to overcome the
Aspirin
(Antiplatelet,
stent thrombosis
prevention)
possibility of unopposed thromboxane-dependent
platelet activation after stopping aspirin with subsequent cardiovascular events (63). In 2 patient series in
which aspirin monotherapy was stopped without
a substitute, higher rates of thrombotic events
occurred (64,65). Of course, a patient group on aspirin
C E N T R A L I L L U S T R A T I O N Double and Triple Antiplatelet Therapy Risks
monotherapy totally differs from the present patients
in AF and PCI
receiving long-term VKA plus clopidogrel therapy.
Nevertheless, in the WOEST trial, the AFCAS trial, and
Patients with atrial fibrillation (AF) who undergo percutaneous coronary intervention
(PCI): combining antiplatelet and anticoagulant therapies in search of an optimal equi-
the Danish and German registries, there was no
librium in between bleeding risk on the one hand and thrombotic and thromboembolic
excess of stent thrombosis in the aspirin-free group
risk on the other.
(6,13–15). Therefore, it is debatable whether this
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Triple Therapy for AF and PCI
VKA and aspirin was associated with significantly
eluting stents were especially chosen in the OPTI-
increased risk for bleeding without a clear reduction
MIZE and RESET trials because of their early vessel
of MACCE (66,67).
healing characteristics (70–74). Third, the OPTIMIZE
The seventh possible pitfall is that the guidelines
trial mostly included patients with stable angina and
recommend BMS placement in both elective and
low-risk ACS while excluding ST-segment elevation
acute settings for AF patients with an indication for
myocardial infarction patients (70). Therefore it
long-term VKA therapy (4,68). However, these rec-
might be too early to change the duration of routine
ommendations were based upon expert opinion in
clopidogrel administration to 3 months.
the absence of data from randomized trials. A recent
subanalysis of the WOEST trial shows no advantage
NEW MEDICATION, ONGOING TRIALS AND
for patients who received a BMS as compared with a
FUTURE PERSPECTIVES
DES. Moreover, the rate of TVR was significantly
lower in patients treated with DES, despite the fact
Although dual therapy with VKA and clopidogrel
that baseline characteristics for this group were less
probably presents a better option than triple therapy,
favorable (such as a higher incidence of diabetes at
there is still much room for improvement with regard
baseline and more American College of Cardiology/
to the prevention of both ischemic and bleeding
American Heart Association type C lesions) (unpub-
events. Therefore, the search for newer and better
lished data). We also know that the rates of TVR and
antithrombotic medication and combinations of these
stent thrombosis are markedly lower after implanta-
drugs continues.
tion of newer-generation DES, such as everolimus-
Over the last several years, numerous new medi-
eluting stents (69), and the difference in the rate of
cations have emerged to challenge the classics. In the
stent thrombosis after DES as compared to BMS seems
PLATO (Study of Platelet Inhibition and Patient Out-
to have disappeared with the newer-generation DES.
comes) trial evaluating 18,624 patients with ACS, the
Finally, recent data suggest that 3 months of DAPT
combination of ticagrelor (a reversible P2Y 12 inhibitor)
might be long enough in some cases instead of the
and aspirin was superior to clopidogrel and aspirin
standard 12 months. In the recent OPTIMIZE (Opti-
(56). Administration of ticagrelor even led to a
mized Duration of Clopidogrel Therapy Following
decrease in mortality. The TRITON–TIMI 38 (Trial to
Treatment With the Zotarolimus-Eluting Stent in
Assess Improvement in Therapeutic Outcomes by
Real-World Clinical Practice) trial, among 3,199 pa-
Optimizing
tients with stable CAD or low-risk ACS treated with
Thrombolysis In Myocardial Infarction 38) trial
zotarolimus-eluting stents, 3 months of DAPT was
showed that in 13,608 patients with ACS undergoing
noninferior to 12 months, without significantly in-
PCI, the combination of prasugrel (a more potent
creasing the risk of stent thrombosis (70). Moreover,
thienopyridine than clopidogrel but similarly an
Platelet
Inhibition
with
Prasugrel–
the EXCELLENT (Efficacy of Xience/Promus Versus
irreversible P2Y12 inhibitor) and aspirin was more
Cypher to Reduce Late Loss After Stenting), PRODIGY
effective than clopidogrel and aspirin, but with an
(Prolonging Dual Antiplatelet Treatment After Grad-
increased number of bleeding events (57).
ing Stent-Induced Intimal Hyperplasia Study), and
Both prasugrel and ticagrelor seem to be good al-
RESET (REal Safety and Efficacy of 3-month dual an-
ternatives to clopidogrel in patients with AF under-
tiplatelet Therapy following Endeavor zotarolimus-
going PCI
eluting stent implantation) randomized trials also
potently and show less interindividual variability
tested different durations of DAPT (3 or 6 months vs.
than clopidogrel. But both the PLATO and TRITON–
12 or 24 months) with multiple DES, and results did
TIMI 38 trials excluded patients with VKA. In a pro-
not show benefits favoring prolonged DAPT (71–74).
spective registry of 377 patients, the combination of
because
they inhibit platelets
more
One can question if patients on long-term OAC
prasugrel, aspirin, and VKA was used by 21 patients
might benefit from a shorter treatment with clopi-
and showed a 4-fold increase in the risk of TIMI minor
dogrel that would surely decrease bleeding risk in this
and major bleeding compared with a regimen of clo-
patient group. But, before adopting a regimen con-
pidogrel, aspirin, and VKA, without any significant
taining 3 months of clopidogrel, some caution is
difference in efficacy (75). We do not have any data
needed. First, a cohort study containing 125,195 pa-
yet on the combinations of VKA plus prasugrel, VKA
tients showed that the bleeding risk is the highest
plus ticagrelor, or triple therapy (VKA plus ticagrelor
during the first 30 days of VKA therapy, with almost
plus aspirin) in AF patients undergoing PCI, but one
1% of all new users admitted to a hospital for hem-
could reasonably fear that combining these more
orrhage during this period (37). Second, it is unclear
potent platelet inhibitors with VKA could lead to
whether this applies to all DES, as zotarolimus-
more bleeding events.
Dewilde et al.
JACC VOL. 64, NO. 12, 2014
SEPTEMBER 23, 2014:1270–80
Triple Therapy for AF and PCI
Over the last decade, non-VKA oral anticoagulants
This study aims to include 2,100 patients to compare
(NOACs) such as dabigatran, rivaroxaban, and apix-
the safety of 2 rivaroxaban treatment strategies
aban have been shown to offer advantages over VKA
versus a dose-adjusted VKA treatment strategy. Pa-
for stroke prevention in patients with AF (76–79).
tients will be treated for 12 months, and the primary
Their potential as antithrombotic therapy after
endpoint is the composite of TIMI major bleeding,
ACS has as subsequently been investigated. The
TIMI minor bleeding, and bleeding requiring medical
ATLAS ACS 2-TIMI 51 (Anti-Xa Therapy to Lower
attention (80). The RE-DUAL PCI (Randomized Eval-
Cardiovascular
Standard
uation of Dual Therapy with Dabigatran vs. Triple
Therapy in Subjects with Acute Coronary Syndrome–
Therapy Strategy with Warfarin in Patients with
Thrombolysis IN Myocardial Infarction trial, for
NVAF that have undergone PCI with Stenting) trial
example, showed that by adding low-dose rivarox-
was also started recently. In this trial, the safety and
aban in 15,526 patients with a recent ACS, the com-
efficacy of 2 dabigatran treatment strategies will be
posite endpoint of cardiac death, MI, and stroke was
tested versus dose-adjusted VKA treatment (81). Un-
reduced, whereas the risk of major and intracranial
fortunately, the superior arm of the WOEST trial (VKA
Events
in
Addition
to
bleeding was simultaneously increased (32). The
and clopidogrel) was left out of both trials (80,81).
APPRAISE 2 (Apixaban for Prevention of Acute
Another trial that is still recruiting patients is the
Ischemic Events 2) trial, in which full-dose apixaban
ISAR TRIPLE (Intracoronary Stenting and Anti-
was added to dual antiplatelet therapy in patients with
thrombotic Regimen: Testing of a Six-Week Versus a
ACS, was halted prematurely, however, due to an
Six-Month Clopidogrel Treatment Regimen in Pa-
excess in major bleeding events without a significant
tients With Concomitant Aspirin and Oral Anticoag-
reduction in ischemic events (33). In the REDEEM
ulant Therapy Following Drug-Eluting Stenting) trial
(RandomizEd Dabigatran Etexilate Dose Finding
in which 600 patients are randomized to a 6-week
Study in Patients With Acute Coronary Syndromes)
versus a 6-month triple therapy regimen after DES
trial, dabigatran in addition to DAPT also resulted in a
implantation. The primary endpoint of ISAR TRIPLE
dose-related increase in bleeding risk without reduc-
is a net clinical benefit endpoint consisting of MACCE
tion of ischemic clinical events (79).
and major bleeding (82).
In AF patients who need PCI, none of these NOACs
has been tested yet. As demonstrated by all of these
CONCLUSIONS
trials, finding the balance between reducing the risk
of
excessively
The efficacy of triple therapy (VKA, aspirin, and clo-
increasing bleeding risk is difficult. The challenge of
thromboembolic
events
without
pidogrel) in AF patients who need to undergo PCI
using NOACs in AF patients who need PCI is just as
with stent placement has never been proven, but this
difficult. First of all, we encounter the problem of
strategy increases bleeding risk significantly. New
finding the optimal NOAC dose for this indication;
evidence, including a randomized controlled trial and
and second, we have to ponder which P2Y12 inhibitor
a real-life nationwide registry of more than 12,000
to prescribe and whether or not to combine it with
patients, showed the great potential of the combina-
aspirin. PIONEER AF-PCI (An Open-label, Random-
tion of VKA and clopidogrel without aspirin to
ized, Controlled, Multicenter Study Exploring Two
improve clinical outcomes in comparison with triple
Treatment Strategies of Rivaroxaban and a Dose-
therapy. Therefore, VKA combined with clopidogrel
Adjusted Oral Vitamin K Antagonist Treatment
seems to be a reasonable alternative to triple therapy
Strategy in Subjects With Atrial Fibrillation Who Un-
in patients on long-term VKA who undergo PCI and
dergo Percutaneous Coronary Intervention) is the
stenting.
first trial to address this issue, although the number
of different possibilities to investigate seems almost
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
unlimited (80). PIONEER AF-PCI is an innovative
Willem J.M. Dewilde, Department of Cardiology,
phase IIb clinical study investigating the safety and
Amphia Hospital, Molengracht 21, 4818 CK Breda, the
efficacy of rivaroxaban in AF patients undergoing PCI.
Netherlands. E-mail: [email protected].
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KEY WORDS acenocoumarol, clopidogrel,
dual antiplatelet therapy, oral
anticoagulation, phenprocoumon,
platelet aggregation